Managing Analytical Procedure Lifecycles: Resolving Longstanding Mass Spectrometry Challenges for Emerging Nitrosamine and NDSRI Impurities

The nitrosamine crisis began in July 2018 when N-nitrosodimethylamine (NDMA) was discovered in valsartan products. The potential carcinogenicity of nitrosamines and nitrosamine drug substance-related impurities (NDSRIs) triggered recalls, global regulatory action, and a significant overhaul of drug quality control to prevent future contamination. In response, FDA laboratories rapidly developed and validated analytical methods for NDSRIs and nitrosamines, primarily using liquid chromatography-mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-MS/MS) techniques.        

The pharmaceutical industries are still facing significant analytical challenges in quantifying NDSRIs and nitrosamines due to their trace-level presence, chemical diversity, and matrix complexity. Additionally, mass spectrometry has not been routinely used in QC environment until recently and the ICH Q2(R1) Validation of Analytical Procedure guideline (2005) did not provide detailed recommendations for mass spectrometry methods. The presentation will discuss best practices for mass spectrometry based on analytical procedures for NDSRIs and nitrosamines based on FDA laboratories’ experience. These best practices and case examples of troubleshooting common analytical challenges shared in this presentation might help industries navigate the complex technical requirements while ensuring patient safety and product quality

Presented by Jinhui Zhang, Chemist at FDA/CDER

Dr. Jinhui Zhang is a Senior Pharmaceutical Scientist at the FDA/CDER. His research at FDA focuses on using advanced mass spectrometry for the characterization of biotherapeutics, complex drug products, as well as bioanalysis in support of clinical pharmacology and bioequivalence. He has given over 60 invited podium presentations at international conferences such as, AAPS, AAPS NBC, ACS, IFPAC etc; and published 50 peer reviewed publications on implementing ICH M10, Q14, Q2(R2) and Q12 guidelines, advanced characterization of complex modalities, clinical and preclinical pharmacokinetics. Dr. Zhang is an associate director advisory committee member of CASSS.

Why Accurate Nitrosamine Data Matters: Key Challenges and Considerations

In any N-Nitrosamine risk assessment it is critical that analytical data used in such assessments is accurate.  Without this it is impossible to determine the extent of the risk or indeed to resolve any issues that threaten the viability of the product concerned. This may seem like an obvious statement and true of any investigation into impurities.  However, the challenge posed by Nitrosamines in terms of their analysis is uniquely challenging, factors such as extreme low levels, artefactual formation all contribute to uncertainty.  The aim of this presentation is to look at such challenges and examine the potential to develop a systematic approach to method development and validation, both in terms of simple N-Nitrosamines and Nitrosamine Drug Substance related impurities (NDSRIs)

Presented by Andrew Teasdale, Principal Consultant at Nelson Labs

Andrew Teasdale PhD has over 30 years’ experience in the pharmaceutical industry as an analytical chemist and within quality assurance and regulatory roles. Recently retired from AstraZeneca, Andrew used to chair AZ’ Impurity Advisory Group.  He has also led a number of Industry groups including being a past chair of the Extractables and Leachable safety Information exchange (ELSIE) and the Joint Pharmaceutical analysis group JPAG) and a member of the Royal Pharmaceutical Society (RSC) science board. He has also led a number of industry expert groups; these include both safety and quality groups within Pharmaceutical Research and Manufacturers of America (PhRMA), European Federation of Pharmaceutical Industries and Associations (EFPIA), Product Quality Research Institute (PQRI). He has also represented EFPIA in ICH Q3C-D-E working groups. Andrew has published several books and papers relating to ICH Q’ guidelines, mutagenic impurities, N-Nitrosamines, extractables and leachables, and other impurity related matters and is the inventor of the purge factor concept. On the personal side, Andrew is a long time Newcastle football fan and enjoys traveling.

Followed by a live question and answer session

Sponsored by Nelson Labs

Nelson Labs is a global leader in microbiological and analytical chemistry testing and advisory services for the medical device and pharmaceutical industries. Nelson Labs serves over 3,000 customers across 13 facilities in the United States, Mexico, Asia, and Europe.  We provide our customers with mission-critical testing services, which assess the quality, effectiveness, and end-to-end sterility of products and, ultimately, the impact of the products on patient safety. These services are necessary for our customers’ regulatory approvals, product releases, and ongoing product performance evaluations.  We have over 900 laboratory tests supporting our customers from initial product development and sterilization validation, through regulatory approval and ongoing product testing for sterility, safety, and quality assurance.  Pharmaceutical lab testing services include microbiology, biocompatibility and toxicology assessments, extractables and leachables evaluations of pharmaceutical containers, sterilization validation, sterility assurance, packaging validation and distribution simulation, and facility and process validation.  We also provide expert advisory services to help customers navigate the regulatory requirements applicable throughout their product’s lifecycle. We are regarded as a best-in-class partner with a strong track record of collaborating with customers to solve complex issues.